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Updated: Jun 24, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
CRISPR activation screens identify the SWI/SNF ATPases as suppressors of ferroptosis
Kamakoti P Bhat1, Jinchu Vijay2, Caroline K Vilas3
1Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
Abstract:
Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase 4) prevents ferroptosis by reducing these lipid peroxides into lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide CRISPR activation screens, we identify the SWI/SNF (switch/sucrose non-fermentable) ATPases BRM (SMARCA2) and BRG1 (SMARCA4) as ferroptosis suppressors. Mechanistically, they bind to and increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output to counter lipid peroxidation and confer resistance to GPX4 inhibition. We further demonstrate that the BRM/BRG1 ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1 mutant cancer cells on BRM. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
Insights
The SWI/SNF ATPases BRM and BRG1 suppress ferroptosis, a cell death pathway. Targeting this pathway can enhance cancer therapies, especially in BRG1-mutant cells.
Area of Science:
- Cellular biology
- Cancer research
- Biochemistry
Background:
- Ferroptosis is an iron-dependent cell death marked by lipid peroxide accumulation.
- Glutathione peroxidase 4 (GPX4) inhibits ferroptosis by reducing lipid peroxides.
- GPX4 inhibition is a cancer vulnerability, necessitating identification of ferroptosis regulators.
Purpose of the Study:
- To identify novel regulators of ferroptosis.
- To explore the therapeutic potential of targeting ferroptosis in cancer.
- To investigate the role of SWI/SNF ATPases in ferroptosis regulation.
Main Methods:
- Genome-wide CRISPR activation screens were employed.
- Chromatin accessibility assays were performed.
- NRF2 transcriptional activity was analyzed.
Main Results:
- BRM (SMARCA2) and BRG1 (SMARCA4) were identified as ferroptosis suppressors.
- BRM/BRG1 increase chromatin accessibility at NRF2 target loci, boosting NRF2 output.
- This mechanism confers resistance to GPX4 inhibition.
- BRG1 mutant cancer cells show enhanced dependency on BRM.
Conclusions:
- BRM and BRG1 act as key suppressors of ferroptosis.
- Targeting ferroptosis via BRM/BRG1 modulation offers a therapeutic strategy.
- Exploiting GPX4 dependency in specific genetic contexts, like BRG1 mutations, can enhance cancer treatment efficacy.
